Our Pipeline

Therapeutic Candidates
Indications
Preclinical
Phase 1
Registrational Trial (Phase 2/3)

ERNA-101*

Oncology

Platinum-Resistant Ovarian Cancer

ERNA-102

Autoimmune Disease

Rheumatoid Arthritis

*Alone or in combination with immunotherapies (CAR-T, bispecific T-cell engagers, checkpoint inhibitors, tumor-infiltrating lymphocytes, etc.) with potential big-pharma collaborators

Rationale for Ovarian Carcinoma as the lead indication for ERNA-001

Despite recent advances in therapy, ovarian carcinoma remains the most lethal of gynecologic malignancies with approximately 13,000 deaths/year (2022) in the USA[1].  High-grade serous carcinoma (HGSOC) represents the most frequent histologic type of ovarian cancer and typically presents at an advanced stage due with symptomology reflecting disseminated intraperitoneal spread:  abdominal pain and distension , difficulty eating, ascites, urinary complaints and shortness of breath[2].  Although these tumors typically respond initially to surgical resection and platinum-based chemotherapy, over 80% of patients recur and greater than 50% of patients will succumb to their disease within 5 years of diagnosis[3].  Interestingly, high baseline levels of proinflammatory cytokines, including Il-7, correlate with an inflamed tumor microenvironment and better PFS following standard-of-care treatment[4].  Thus, there remains a significant unmet medical need for patients with platinum-resistant ovarian carcinoma and a rationale for new therapeutics to enhance inflammation in the ovarian tumor microenvironment.

Ovarian carcinoma is thought to be immunogenic based on a high frequency of PD-1 and PD-L1 expression, the presence of TILS and the correlation of TILs with improved clinical outcomes[5-10].  Surprisingly, the response to ICIs has been underwhelming.  In a Phase 2 trial with 366 Ovarian Cancer patients testing the efficacy of pembrolizumab (KeytrudaTM), objective response rates were 7.4% overall[11].  Results were similarly disappointing in the Phase 3 trial with nivolumab (OptivoTM)in platinum-resistant ovarian cancer (8% ORR) without any observed improvement in either PFS or OS[12].  A likely reason contributing to this overall lack of meaningful clinical response to ICIs is the prevalence of immunosuppressive myeloid cells, regulatory T cells (Tregs) and immunosuppressive cytokines within the HGSOC tumor microenvironment, leading to both immune cell exclusion and dysfunction [13-15].  

One of our collaborators, Dr. Michael Andreeff (MD Anderson), has pioneered the use of gene-modified MSCs as a potential therapy for ovarian cancer.  Dr. Andreeff and colleagues demonstrated in several experimental mouse tumor models that intraperitoneal injection of MSCs engineered to express interferon beta (INFβ) were capable of engrafting into peritoneal tumor deposits with persistent secretion of INFβ, both in human xenograft tumor models and in a syngeneic ID8 tumor model using immunocompetent mice.  A significant improvement in tumor burden and survival was observed in all of these experimental systems[16].  A subsequent single-site Phase 1 clinical trial was initiated at MD Anderson in patients with advanced platinum-refractory ovarian cancer to evaluate the safety, feasibility and tumor response to intraperitoneal-administered INFβ-MSCs.  In the first cohort, INFβ-MSCs were dosed weekly with 1x105 MSCs/kg with a total of 4 doses.  Histologic analysis confirmed that the INFβ-MSCs were able to colonize tumor sites and express INFβ locally[17].  Although no objective responses were identified at this first dose level, this study demonstrates the feasibility of intraperitoneal delivery of MSCs as a treatment modality in patients with advanced ovarian cancer.

  1. Siegel, R.L., et al., Cancer statistics, 2022. CA Cancer J Clin, 2022. 72(1): p. 7-33.
  2. Goff, B., Symptoms associated with ovarian cancer. Clin Obstet Gynecol, 2012. 55(1): p. 36-42.
  3. Peres, L.C., et al., Invasive Epithelial Ovarian Cancer Survival by Histotype and Disease Stage. J Natl Cancer Inst, 2019. 111(1): p. 60-68.
  4. Torkildsen, C.F., et al., New immune phenotypes for treatment response in high-grade serous ovarian carcinoma patients. Front Immunol, 2024. 15: p. 1394497.
  5. Hao, J., et al., Prognostic impact of tumor-infiltrating lymphocytes in high grade serous ovarian cancer: a systematic review and meta-analysis. Ther Adv Med Oncol, 2020. 12: p. 1758835920967241.
  6. Ovarian Tumor Tissue Analysis, C., et al., Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer. JAMA Oncol, 2017. 3(12): p. e173290.
  7. Sato, E., et al., Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A, 2005. 102(51): p. 18538-43.
  8. Bobisse, S., et al., Sensitive and frequent identification of high avidity neo-epitope specific CD8 (+) T cells in immunotherapy-naive ovarian cancer. Nat Commun, 2018. 9(1): p. 1092.
  9. Nelson, B.H., et al., Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer. J Clin Invest, 2024.
  10. Shalaby, A., et al., Correlation of PD-L1 expression with different clinico-pathological and immunohistochemical features of ovarian surface epithelial tumors. Clin Transl Oncol, 2024.
  11. Varga, A., et al., Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Gynecol Oncol, 2019. 152(2): p. 243-250.
  12. Hamanishi, J., et al., Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA). J Clin Oncol, 2021. 39(33): p. 3671-3681.
  13. Hensler, M., et al., M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer. J Immunother Cancer, 2020. 8(2).
  14. Fu, W., Q. Feng, and R. Tao, Machine learning developed a fibroblast-related signature for predicting clinical outcome and drug sensitivity in ovarian cancer. Medicine (Baltimore), 2024. 103(16): p. e37783.
  15. Desbois, M., et al., Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nat Commun, 2020. 11(1): p. 5583.
  16. Dembinski, J.L., et al., Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer. Cytotherapy, 2013. 15(1): p. 20-32.
  17. Olson, A., et al., A Phase I Trial of Mesenchymal Stem Cells Transfected with a Plasmid Secreting Interferon Beta in Advanced Ovarian Cancer. Biology of Blood and Marrow Transplantation, 2018. 24(3): p. S473.

Our Collaborations